How Do Cells Know Their Location And Their Role In The Body?

The capacity to specialize is central to our society. People spend decades getting very good at a small number of things. We might venerate the Da Vincis that can excel in multiple areas at once, but if we all tried it society would grind to a halt because almost everything would be done badly. Of course, that doesn’t stop the online peanut gallery who think they know more about everything from immunology to climatology than those who have made those things.

Any animal or plant is like a civilization. It took three billion years (probably) between life emerging and cells developing the capacity to organize collectively to produce more advanced organisms. Along with external factors like shortages of oxygen, part of the problem was probably working out how to ensure each cell ended up in the right role. So what was the magic solution that allowed us to become a collective of 30 trillion cells all doing their appropriate job?

The answer is still unfolding, but central to it are gradients created by certain molecules, known as morphogens. A cell’s DNA is encoded to respond both to the abundance of a morphogen, and the direction where a specific morphogen is getting more, or less, abundant. When these conditions are right, these morphogens will trigger the cell to express genes that make it the become what is necessary for its location – for example reaching its potential to become a liver or kidney cell.

For some cells, this information only needs to be rough, but Professor Arthur Lander of the University of California, Irvine, notes that others need far more precision. If the body has suffered an injury, cells need to know exactly where they are in relation to the damage to know how best to fix it.

This means morphogens need to be not only constantly created, but also continuously destroyed, to maintain a gradient clear enough a cell can use it for guidance. Certain cell receptors take up the morphogens and destroy them until a balance is struck that leaves a stable gradient.

However, morphogen gradients can’t be the whole story. For one thing, keeping the gradient perfectly stable is an almost impossible task. If cells lost direction every time morphogens got a little too abundant in one place, things could go badly wrong. Given how often human-made measuring devices produce errors, it’s also a fair bet that cells can’t always read their environment perfectly. 

Cells have developed some very clever ways of dealing with the measurement side. For example, some cells degrade the very morphogens they rely on to tell them their place. It’s a way to get a sort of second opinion. If you’re unsure which way the gradient points, destroy the morphogens around you and wait for a signal to come down the line from the source, providing a clearer picture of where you are. This may, however, make the pattern harder to read for other cells further from the source, at least temporarily.

As Lander notes, this is one example of the complex set of trade-offs for cells relying on these gradient measurements, balancing questions of morphogen abundance. “Strategies that improve performance in one arena typically degrade it in another,” he notes.

Alan Turing (who coined the term morphogen) noted that complex patterns like a leopard’s spots could be produced by just two balancing each other as an exhibitor and inhibitor. The idea was widely accepted, but only proven in 2014, 60 years after Turing’s death.

Identifying Morphogens

Despite the idea of morphogens being proposed in the early 20^th Century and developed by Turing in the 1950s, the first wasn’t identified until 1980, for which Christiane Nüsslein-Volhard was awarded the 1995 Nobel Prize for Medicine. Even that was only in fruit flies, with human morphogens identified later.

With so many organs to make in a mammalian body, plenty of different morphogens are needed so a cell knows which it needs to become part of. The initial morphogen is retinoic acid, which identifies one end of the embryo as the head, and one as the rear, telling cells where they fit in this arrangement. It triggers Hox genes in cells to make them develop in a manner appropriate to their location. 

Biology being conservative, once it has initiated the process of the body’s shape developing, retinoic acid takes on new roles in immune functioning and sperm production. Noe the developing body knows its ass from its elbow, as it were, other morphogens take over, notably the sonic hedgehog protein responsible for the organization of the central nervous system and limbs.

At least 13 bone morphogenic proteins are known which, as the name suggests, control the building of bones by instructing a cell where it sits relative to others, and therefore the form it must take. They also control the formation of cartilage, and influence many other tissues in the body.

Some morphogens have only been discovered quite recently, so it’s likely there are more yet to be found.

Even with the list incomplete, many cells have been shown to respond to several different morphogen gradients, particularly in complex organs such as the brain. 

Biological Back-ups

Even this is not enough to ensure all cells find their place, so cells also share information with each other, a process that has been observed in the development of fruit fly wings. 

Despite all these mechanisms, we know things sometimes go wrong. Strange tumors (teratomas) develop when cells turn into something they should not, like teeth or miniature brains, despite being located somewhere very different. It’s the biological equivalent of untrained people who think they know more than the specialists. The body has methods to identify when cells might be on the verge of making a mistake, for example by comparing the ratio of different morphogens, using an imbalance as a warning to check for errors.

As well as molecules, cells may use electric fields, or mechanical signals to turn gene expression up or down. The extent to which this happens also remains unknown.